Until recently, thyroid cancer (TC) has been largely ignored in the US because the majority of thyroid cancer cases have very good prognosis, with 5-year survival rates of approximately 96%, but those diagnosed at late stages have a devastating 5-year survival rate of fewer than 60%. Thus, despite advances on scientific and clinical fronts, advanced thyroid cancers remain incurable. Alarmingly, TC has the fastest rising incidence rates in women, and the second fastest in men with an annual percentage change of approximately 5%, making thyroid cancer the sixth most common cancer in women. For individuals who present with early-stage disease, there is no accurate marker(s) to predict whether they will develop metastatic or recurrent disease. Additionally, it is virtually impossible to definitively differentiate follicular thyroid cancer (FTC) from a benign follicular proliferatio (follicular adenomas {FA}) preoperatively (by fine needle aspiration ({FNA}) due to morphologic overlap. A single false-negative FNA can significantly delay surgical treatment, leading to higher rates of vascular and capsular invasion and advanced stage disease, making it incurable. The present challenge is to obtain reliable, preoperative markers that differentiate benign and malignant thyroid nodules, to detect early TC, to improve discrimination of adenoma, papillary thyroid cancer (PTC), and FTC so as to delineate thyroid subtypes in order to improve patient management. Over the past 15 years, the application of molecular technologies has focused on genetic events. Methylation of thyroid-specific genes, such as those for sodium/iodide symporter (NIS) and thyroid-stimulating hormone receptor have implications in clinical radioiodine treatment of thyroid cancer. A candidate gene approach to identify methylation markers specific to thyroid cancer types and subtypes would be an essential first step for TC-specific biomarkers. The underlying hypothesis of this research is that a candidate gene approach will identify methylated genes relevant to TC. We will evaluate 21 candidate genes reported to be hypermethylated in TC for promoter hypermethylation in a retrospective cohort of 320 cases comprising of 80 PTC, 80 FTC, 80 follicular adenomas (benign) and 80 normal (control) thyroid tissues. These will be useful as predictors of outcome (early versus late stage, recurrence and survival), to potentially improve discrimination of adenoma, PTC, and FTC, to delineate thyroid subtypes (conventional PTC vs PTC-follicular variant and FTC vs its variant FTC-Hurthle), as well as differentiate follicular thyroid carcinoma from a benign follicular proliferation preoperatively. PUBLIC HEALTH RELEVANCE: Advanced thyroid cancer (TC) has a devastating 5-year survival rate and remains incurable. Also, it is virtually impossible to definitively differentiate follicular thyroid cancer (FTC) from benign thyroid disease. This research will identify thyroid-specific DNA methylation markers as predictors of outcome (early versus late stage, recurrence and survival), to potentially improve discrimination of adenoma, papillary thyroid cancer (PTC), and FTC, to delineate thyroid subtypes (conventional PTC vs PTC-follicular variant and FTC vs its variant FTC-Hurthle), as well as differentiate FTC from a benign follicular proliferation preoperatively.